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Diverging Network Architecture of the C. elegans Connectome and Signaling Network

Sophie Dvali1, Caio Seguin2,3, Richard Betzel4,5, and Andrew M. Leifer1,6,*

  • *Contact author: leifer@princeton.edu
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PRX Life 3, 033021 – Published 10 September, 2025

DOI: https://doi.org/10.1103/6wgv-b9m6

Abstract

The connectome describes the complete set of synaptic contacts through which neurons communicate. While the architecture of the Caenorhabditis elegans connectome has been extensively characterized, much less is known about the organization of causal signaling networks arising from functional interactions between neurons. Understanding how effective communication pathways relate to or diverge from the underlying structure is a central question in neuroscience. Here we analyze the modular architecture of the C. elegans signal propagation network, measured via calcium imaging and optogenetics, and compare it to the underlying anatomical wiring measured by electron microscopy. Compared to the connectome, we find that signaling modules are not aligned with the modular boundaries of the anatomical network, highlighting an instance where function deviates from structure. However, we find that some of the most striking features of the anatomical network are preserved, as exemplified by the pharynx, which is delineated into a separate community in both anatomy and signaling. We analyze the cellular compositions of the signaling architecture and find that its modules are enriched for specific cell types and functions, suggesting that the network modules are neurobiologically relevant. Lastly, we identify a “rich club” of hub neurons in the signaling network. The membership of the signaling rich club differs from the rich club detected in the anatomical network, challenging the view that structural hubs occupy positions of influence in functional (signaling) networks. The only overlap between the two rich clubs is given by neurons AVEL/R, which have some of the highest degrees in the anatomical network, again illustrating the preservation of the most pronounced features of the network. Our results provide new insight into the interplay between brain structure, in the form of a complete synaptic-level connectome, and brain function, in the form of a system-wide causal signal propagation atlas.

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PRX Life 3, 033021– Published 10 September, 2025
  • Received 4 March 2025
  • Accepted 11 August 2025
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